Protein-protein interactions play critical roles in almost all aspects of cellular function and intercellular communication. The proposed research is directed at improving our understanding of the fundamental contributions to the free energy of protein-protein interactions, and using this understanding to redesign protein-protein interaction specificity and to predict the structures of protein-protein complexes from the structures of the unbound partners. The research will involve an integrated combination of computational and experimental approaches. Feedback from the design and prediction studies will guide the development of an improved physical model for the free energy of protein-protein interactions. The design and prediction methods should add significant value to the large number of monomeric protein structures being determined in current large scale structural genomics efforts by allowing them to be assembled into functionally important complexes, and will provide powerful tools for teasing apart complex interaction networks by reprogramming the specificities of individual pairs of interacting proteins.